Atherosclerosis results from vascular injury induced by multiple insults including hypercholesterolemia, diabetes, smoking, and hypertension. Atherosclerosis is responsible for approximately 50% of all deaths in the developed world (Davis et al., J Thromb Haemostas. 2003; 1:1699-1709). Depending on the degree of narrowing and the specific vessel(s) involved, atherosclerosis can lead to pathologic conditions throughout the body, including: coronary artery disease, cerebrovascular disease, peripheral vascular disease, and renovascular disease.
Interventional treatments for atherosclerotic lesions include percutaneous procedures, such as balloon angioplasty with or without stenting, and surgical procedures, such as vascular bypass of a stenotic lesion. Coronary artery bypass grafting (CABG) utilizes arteries (e.g., the left internal mammary artery) and/or veins (e.g., the saphenous vein) as the bypass conduit. Non-cardiac bypass procedures, e.g., femoral-popliteal artery bypass, also utilize synthetic conduits.
Vascular interventions such as atherectomy, angioplasty with or without stent placement and vascular bypass are accompanied by vascular injury to the vessel being intervened upon, nearby blood vessels, and/or, in the case of autologous conduit grafting, in the vascular conduit. This injury can lead to early (subacute) thrombosis (SAT) or, later, intimal hyperplasia. Subacute thrombosis and intimal hyperplasia are significant concerns following angioplasty and stent placement, and can lead to restenosis (U.S. Pat. No. 6,723,120). Stenotic lesions that have been dilated by angioplasty restenose in up to 50% of cases (U.S. Pat. No. 6,730,313). Following CABG, the 5 and 10-year patency rates of saphenous vein grafts are approximately 74% and 41%, respectively (Barner et al., J Thorac Cardiovasc Surg. 1985; 90:668-75). Depending on the location of the affected vessel, restenosis can result in myocardial infarction, stroke or limb loss.
Damage to the vascular endothelium compromises the balance between antithrombotic and prothrombotic factors and results in thrombus formation (Davis, et. al.). The endothelium plays key roles in the vascular response to injury, including the regulation of leukocyte adhesion, platelet aggregation and adhesion, and hemostasis/thrombosis. In performing these functions, the endothelium expresses and responds to cytokines, chemokines, and cell adhesion molecules. Vessel injury results in endothelial damage that compromises the endothelium's normal physiological role and triggers an inflammatory response including platelet activation, leukocyte infiltration into the vessel wall, smooth muscle cell proliferation and migration, and extracellular matrix deposition (Davis et al.).
Early graft failure is related to thrombosis and inflammation. A clinical study of patients after cardiac surgery showed that CABG induces marked pro-thrombotic and inflammatory responses, which persist for at least one week (Li, et al., J Thromb Haemostas. 2003; 1(3):470(abstract)). Vascular injury also triggers a remodeling process characterized by the loss of the inner cellular coating of the vessel (intima) and induction of proliferation and migration of smooth muscle cells from the middle layer of the vessel wall (media). These smooth muscle cells migrating into the intima form a “neointima.” The growth of the neointima and deposition of extracellular matrix ultimately results in an abnormally thick inner layer (intimal hyperplasia) and consequent narrowing of the vessel lumen (restenosis). Thus, vessel injury can result in subacute thrombosis or intimal hyperplasia, or both.
Mitogen-activated protein kinases (MAPK) have been identified as key intracellular signaling mediators responsible for the cellular proliferation, migration, and apoptosis involved in vascular remodeling (Bogoyevitch M A, Cardiovasc Res. 2000; 45:826-42). Three major MAPK pathways have been characterized: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (JNKs), and stress-activated p38MARK. The ERK pathway is predominately activated following the interaction of growth factors with their specific cell tyrosine kinase receptors. JNK and p38MAPK are highly responsive to stress stimuli (Bizekis, et al., J Thorac Cardiovasc Surg. 2003; 126:659-65). MAPKs are activated upstream in the MAPK pathway by kinases (MAPK kinases) known as MEKs (Milella et al., J Clin Invest. 2001; 108(6):851-859). Studies on cultured endothelial and smooth muscle cells or on in vivo injured arteries have linked MAPK activation to cell proliferation, migration, and apoptosis. Saphenous vein excision and preparation for grafting result in activation of ERKs and JNKs. Id.
The synthetic MAPK pathway inhibitor PD98059, an inhibitor of the ERK-1/2 pathway at the MEK-1/2 level, has been shown to inhibit ERK activation and medial cell proliferation when delivered pre- and post-operatively to rats with balloon-injured carotid arteries (Koyama et al., Circ Res. 1998; 82:713-21). However, this inhibitory effect was relatively modest and no conclusions were drawn about the efficacy of such treatment in reducing the overall hyperplastic response to arterial injury.
Considerable effort has been directed to preventing or reducing restenosis after vascular interventional treatment. For example, drug-eluting stents have been used to minimize coronary artery restenosis following atherectomy and balloon angioplasty. Paclitaxol and rapamycin, which inhibit cell proliferation, have been have been used for coating coronary stents. These cytostatic drugs slowly elute from the stent into the vessel wall. U.S. Pat. No. 5,283,257 describes a method for using mycophenolic acid to inhibit intimal thickening. U.S. Pat. No. 5,288,711 describes a combination of rapamycin and heparin to treat hyperproliferative vascular disease. U.S. Pat. Nos. 5,516,781 and 5,646,160 describe the administration of rapamycin alone or in combination with mycophenolic acid using a vascular stent. The problem with using antiproliferative drugs relates to their toxicity. Therapeutically effective doses of these drugs are also highly toxic when they are released into the systemic circulation. Recent case reports have also raised concerns about the long-term side effects of coated stents that elute cytotoxic drugs (McFadden et al., Lancet 2004; 364:1519-1521). Thus, it has been suggested that in certain cases the use of bare metal or non-coated stents would be preferable to toxic drug-eluting stents (Eisenberg, Lancet 2004; 364:1466-1467).
Attempts to prevent the onset, or to mitigate the effects, of intimal hyperplasia have also included, for example, systemic treatment with antiplatelet agents (e.g. aspirin, arachidonic acid, prostacyclin), antibodies to platelet-derived growth factors, and antithrombotic agents (e.g. heparin, low molecular weight heparins) (see, Ragosta et al. Circulation 1994; 89:11262-127). Clinical trials utilizing these agents, however, have shown little effect on the rate of restenosis (Schwartz, et al., N. Engl. J. Med. 1988; 318:1714-1719; Meier, Eur. Heart J. 1989; 10 (suppl G):64-68). In both angioplasty and vascular reconstructive surgery, drug infusion near the site of stenosis has been proposed as a means to inhibit restenosis. For example, U.S. Pat. No. 5,558,642 describes drug delivery devices and methods for delivering pharmacological agents to the vessel wall in conjunction with angioplasty.
Methods of providing therapeutic substances to the vascular wall by means of drug-coated stents have also been proposed. For example, methotrexate and heparin have been incorporated into a cellulose ester stent coating. The drug treated stent, however, failed to show a reduction in restenosis when implanted in porcine coronary arteries (Cox et al., Circulation 1991; 84:1171). Implanted stents have also been used to carry thrombolytic agents. For example, U.S. Pat. No. 5,163,952 discloses a thermal memoried expanding plastic stent device, which can be formulated to carry a medicinal agent by utilizing the material of the stent itself as an inert polymeric drug carrier. U.S. Pat. No. 5,092,877 discloses a stent of a polymeric material which can be employed with a coating that provides for the delivery of drugs. U.S. Pat. No. 5,837,313 discloses a method of coating an implantable open lattice metallic stent prosthesis with a drug releasing coating.
Other patents directed to devices utilizing biodegradable or biosorbable polymers include, for example, U.S. Pat. No. 4,916,193 and U.S. Pat. No. 4,994,071. U.S. Pat. No. 5,304,121 discloses a coating applied to a stent consisting of a hydrogel polymer and a preselected drug, such as a cell growth inhibitor or heparin. Drugs have also been delivered to the interior of vascular structures by means of a polyurethane coating on a stent (U.S. Pat. No. 5,900,246).
The problem of restenosis due to subacute thrombosis and intimal hyperplasia following vascular interventional procedures remains a problem, which results in a high incidence of significant complications and even death. The present invention provides methods and devices, which address the problem of restenosis after vascular interventional procedures.